Method for the purification of an alpha-hydroxy acid on an industrial scale

ABSTRACT

The present invention relates to a method for the purification of an α-hydroxy acid on an industrial scale, in which the method involves: (a) subjecting an aqueous stream containing mainly α-hydroxy ( 1 ) to an extraction step, with the formation of an aqueous place containing mainly α-hydroxy acid ( 2 ), (b) concentrating the aqueous phase containing mainly α-hydroxy acid ( 2 ) by means of evaporation of water under reduced pressure, with the formation of a concentrated α-hydroxy acid solution in water ( 3 ), and (c) subjecting the concentrated α-hydroxy acid solution ( 3 ) to a crystallization, with formation of pure α-hydroxy acid ( 4 ), where (i) the concentrated α-hydroxy acid solution ( 3 ) is directly cooled in a melting crystallization device, and/or (ii) the concentrated α-hydroxy acid solution ( 3 ) is diluted with water and crystallization is brought about in one or more cooling crystallization devices and/or evaporative crystallization devices, and/or (iii) crystallization is brought about in one or more adiabatic crystallization devices.

[0001] The present invention relates to a method for the purification ofα-hydroxy acids, in particular lactic acid or glycolic acid, on anindustrial scale, as well as to products of the utmost chiral puritywhich can be obtained by this method, and to applications thereof.

[0002] Lactic, acid is usually marketed as a dilute or concentratedsolution because lactic acid has a strong tendency to formintermolecular esters (dimeric and polymeric lactic acid). In addition,lactic acid (even very pure lactic acid) is strongly hygroscopic. Thepurification of lactic acid (The racemic mixture and in particular theenantiomers of lactic acid) on an industrial scale is a complicated anddifficult process according to the prior art.

[0003] It is known how to produce lactic acid, or 2-hydroxypropionicacid, in a fermentative manner. In general the fermentative productionof lactic acid includes first of all a fermentation step in which acarbohydrate-containing substrate such as glucose or sucrose isconverted to lactic acid by a suitable microorganism. Knownmicroorganisms producing (S)-lactic acid are various bacteria of thegenus Lactobacillus, such as Lactobacillus casei for example. Inaddition microorganisms are also known which produce (R)-lactic acidselectively. The aqueous fermentation product is then processed in orderto obtain lactic acid. The usual industrial processing path generallyconsists of separation of the biomass followed by acidification,purification and concentration.

[0004] In the case of (S)-lactic acid the lactic acid so obtained issufficiently pure to be processed in foods for human consumption. (S) or(R)-lactic acid which is ultimately obtained by this usual method can be98% enantiomerically pure or even higher (i.e. 98% or more of the lacticacid present consists of the (S) or (R) enantomer). The product stillcontains residual sugars, however. The product is also yellow in colourand on heating this becomes brown to black through decomposition ofimpurities. Moreover, in the case of (S)-lactic acid, the organolepticproperties often leave something to be desired. The lactic acidenantiomer is thus moderately suitable for application in foods, but onthe whole not suitable for pharmaceutical applications and for synthesisof chiral compounds.

[0005] The purity of the product can be increased by esterificationfollowed by hydrolysis, so that it is suitable for pharmaceuticalapplications. As a result of this esterification/hydrolysis, however,the enantiomeric purity decreases and the lactic acid still contains asmall amount of the alcohol which bas been used in the esterification.Examples of other methods for the purification of lactic acid includesubjecting aqueous solutions of lactic acid to one or more extraction,(steam) distillation and/or evaporation steps. electrodialysis steps andcrystallizations (see for example Ullmans Encyklopadie der TechnischenChemie, Verlag Chemie GmbH, Weinheim, fourth edition, Part 17, pages 1-7(1979); H Benninga, “History of Lactic Acid Making ”, Kluwer AcademicPublishers, Dordrecht-Boston-London (1990) C. H. Holten, “Lactic Acid;Propertes and Chemistry of Lactic Acid and Derivatives”, Verlag ChemieGmbH, Weinheim (1971); The Merck Index, Merck & Co., Inc., eleventhedition page 842 (1989); Rommp Chemie Lexicon, G. Thieme Verlag,Stuttgart and New York ninth edition, Part 4, pages 2792-2893 (1991) andthe Netherlands patent applications 1013265 and 1013682.

[0006] In German Patent 593,657 (granted on 15 Feb. 1934) a laboratoryexperiment is described in which an aqueous solution of lactic acid,which contained an excess of the (S) component and practically no lacticacid anhydride, was concentrated by means of a thin-film evaporationtechnique, if necessary at reduced pressure. The concentrated lacticacid solution was then rapidly cooled, with formation of crystals. Afterthat the crystals were separated from the mother liquor, washed withether and repeatedly recrystallized from ethyl acetate or chloroform ora comparable solvent until the crystals showed a sharp melting point of53° C. The chiral purity or the enantiomeric excess and the colour arenot reported.

[0007] In H. Borsook, H. M. Huffman, Y-P. Liu, J. Biol. Chem. 102,449-460 (1933) a laboratory experiment is described in which an aqueousmixture, which contained 50 per cent lactic acid with an excess of(S)-lactic acid, 30 per cent lactic acid anhydride and lactic acid dimerand 15per cent water, was subjected to fractional distillation atapproximately 0.13 mbar and 105° C. The middle fraction was thendistilled again and after that cooled in an ice/salt bath with formationof a solid crystal mass. It is reported that the distillation has to beperformed with small quantities, because with larger quantities there isa big loss of product as a result of the long heating time. The solidcrystal mass was then recrystallized three times from an equal volume ofequal quantities of diethyl ether a diisopropyl ether, and the crystalswere isolated and died at room temperature in a vacuum drier. In thisway it was possible to obtain (S)-lactic acid with a melting point of52.7-52.8° C. which contained less than 0.1 per cent impurities such aswater, lactic acid anhydride or lactic acid dimer. The chiral purity orthe enantiomeric excess and the colour of (S)-lactic acid are notreported.

[0008] In L. B. Lockwood, D. E. Yoder, M. Zienty, Ann. N.Y. Acad. Sci.119, 854 (1965) the distillation and crystallization of lactic acid on alaboratory scale is also described, the melting point of the opticallypure lactic acid obtained being 54° C. The colour is not reported.

[0009] In 1934 the crystallization of lactic acid was investigated byBoehringer Ingelheim, but this method was not found to give goodresults, owing to problems with the purification and further treatment.After the Second World War, however, it turned out that BoehringerIngelheim was able to produce lactic acid for pharmaceuticalapplications on a scale of about 12 to 15 tons per month, with a yieldof about 77 to 86 per cent. In this process an aqueous solution oflactic acid was purified by means of steam distillation at reducedpressure (about 13 mbar), followed by crystallization at −25° C., afterwhich the crystals were dissolved in water and the solution was treatedwith potassium ferrocyanide (to remove heavy metals) and activatedcharcoal. The chiral purity or the enantiomeric excess or otherproperties such as colour and odour of the (S)-lactic acid so producedare not known (see H. Benninga, “History of Lactic Acid Making”, KluwerAcademic Publishers, Dordrecht-Boston-London, pages 347-350 (1990)).

[0010] Crystalline (S)-lactic acid has been marketed by, for example.Fluka and Sigma with purities of more than 99% (see for example M. L.Buszko, E. R. Andrew, Mol. Phys. 76, 83-87 (1992) and T. S. Ing, A. W.Yu, V. Nagaraja, N. A. Amin, S. Ayache, V. C. Gandhi, J. T. Daugirdas,Int. J. Artif. Organs 17, 70-73 (1994)). Crystalline (S)-lactic acidwith a water content of less than 1 per cent by weight is known from EPA 563,455 (see Example 1). The crystal structure of lactic acid isdecribed in A. Schouten, J. A. Kanters, J. van Krieken, J. Mol. Struct.323, 165-168 (1994).

[0011] Lactic acid can also be obtained in a synthetic manner. This isknown. The product of the synthetic production method, however, isracemic mixture which thus contains (S)-lactic acid and (R)-lactic acidin equal quantities. It is true that the separate enantiomers can beseparated by means of known techniques, such as diastereoisomerseparation techniques, where one of the enantiomers crystallizes out asa salt and this salt is then converted back to the enantiomeric lacticacid, but the enantiomeric product finally obtained will inevitablystill contain significant quantities of the other enantiomer.

[0012] In European Patent Application 552,255 it is reported thatglycolic acid of industrial quality can be crystallized by putting asolution thereof in a freezer, giving rise to crystals which arefiltered off. It will be clear that such a method is unsuitable forbeing carried out or an industrial scale. Such a method is also appliedin DE A 2,910,975.

[0013] In WO 00/56693 a method is described for the purification oflactic acid on an industrial scale, the method involving; (a) thedistillation under reduced pressure of a concentrated acid solution witha total acid content of at least 95% by weight and a monomeric lacticacid content of at least 80% by weight, calcuated in terms of theconcentrated lactic acid solution, and with a ratio of the lactic acidenantiomers not equal to 1, and (b) subjecting the distilled lactic acidsolution to a crystallization, with formation of pure lactic acid, wherethe pure lactic acid has a total acid content of at least 99% by weight,a monomeric lactic acid content of at least 98% by weight, a chiralpurity of 99% or more, calculated in terms of the total quantity of purelactic acid, a colour of not more than 10 APHA units and an acceptableodour.

[0014] Disadvantages of this method are that step (a) produces aquantity of residue which is of the order of 5-10% by weight of totalquantity of lactic acid that is present in the feed. The yield, althoughnot low, can be improved Step (b) of this method provides about 45% byweight of end product, calculated in terms of the feed of step (a), andapproximately 45% by weight of mother liquor, which is relatively pure.

[0015] The present invention aims to improve the yield of the methodaccording to WO 00/56693, in particular the yield of step (a). Inaddition, it has been found that not only lactic acid but also otherα-hydroxy acids such as glycolic acid can very effectively be purifiedby the method according to the present invention.

[0016] The present invention therefore relates to a method for thepurification of an α-hydroxy acid on an industrial scale (i.e. a scaleof at least 1000 tons per annum), with the method involving:

[0017] (a) subjecting an aqueous stream containing mainly α-hydroxy acid[1] to an extraction step, with the formation of an aqueous phasecontaining mainly α-hydroxy acid [2],

[0018] (b) concentrating the aqueous phase containing mainly α-hydroxyacid [2] by means of evaporation of water under reduced pressure, withthe formation of a concentrated α-hydroxy acid solution in [3], and

[0019] (c) subjecting the concentrated α-hydroxy acid solution [3] to acrystallization, with formation of pure α-hydroxy acid [4], where thepure α-hydroxy acid has a total acid content of at least 99% by weight,a monomeric α-hydroxy acid content of at least 98% by weight and, ifapplicable, a chiral purity of 99% or more, calculated in terms of thetotal quantity of pure α-hydroxy acid, and a colour of not more than 10APHA units and an acceptable odour.

[0020] An α-hydroxy acid means a carbonic acid which is substituted withα-hydroxy group on the α carbon atom. The general formula of anα-hydroxy acid is therefore:

[0021] where R is a hydrogen atom, a C₁-C₅ alkyl group (preferably amethyl group), a C₆-C₁₂ aryl group or a heterocyclic cycloalkyl or -arylgroup. The α-hydroxy acid according to the invention is preferablylactic acid (R is methyl) or glycolic acid (R is hydrogen) and is inparticular lactic acid.

[0022] It has been found that the yield of this method is higher thataccording to WO 00/56693. In step (a) of the method according to thepresent invention there is considerably less loss than in step (a) ofthe method according to WO 00/56693, i.e. less than 5% by weight of theα-hydroxy of the feed, calculated in terms of the whole feed, is lost asraffinate. Step (b) of the present method is also described in WO00/56693 for the preparation of the feed of step (a) of the methoddescribed therein. In addition, step (c) of the present method producesa mother liquor which is relatively pure and can easily be purified toα-hydroxy acid for applications which require less pure product e.g.foods. On the other hand, the α-hydroxy acid which is obtained by thepresent method is extremely pure and highly suitable for pharmaceuticalapplications.

[0023] According to the invention, step (a) comprises the followingcomponent steps:

[0024] (i) subjecting an aqueous stream containing mainly α-hydroxy acid[1] to a first extraction step, where the aqueous stream containingmainly α-hydroxy acid [1] is brought into contact with a stream which ismainly insoluble in water and which contains an extraction agent [5],with the formation of an organic phase containing mainly α-hydroxy acidand extraction agent [6] and a first aqueous phase containing mainlycontaminants [7], and

[0025] (ii) subjecting the organic phase containing mainly α-hydroxyacid and extraction agent [6] to a second extraction step, where theorganic phase containing mainly α-hydroxy acid and extraction agent [6]is brought into contact with an aqueous stream [8] with the formation ofan aqueous phase containing mainly α-hydroxy acid [2] and an organicphase containing mainly extraction agent [9], with the organic phasecontaining mainly extraction agent [9]being fed back to step (i).

[0026] The aqueous stream containing mainly α-hydroxy acid [1]preferably contains 0.1 to 25% by weight α-hydroxy acid, calculated interms of the whole stream.

[0027] The aqueous phase containing mainly α-hydroxy acid [2] preferablycontains 0.1 to 25% by weight α-hydroxy acid, calculated in terms of thewhole aqueous phase, and has a colour which is preferably not more than100 APHA units and in particular not more than 60 APHA units. On theother hand, [2] can be a concentrated stream which contains 30 to 80% byweight, preferably 30 to 50% by weight α-hydroxy acid, calculated interms of the whole stream, with this stream having a colour which ispreferably not more than 200 APHA. If such a concentrated stream [2] isapplied, this has the advantage that the first aqueous phase containingmainly contaminants [7] can be discharged without further purificationor further treatment.

[0028] The concentrated α-hydroxy acid solution [3] preferably has atotal acid content of at least 70% by weight, more preferably at least80% by weight and in particular at least 85 to95% by weight, calculatedin terms of the whole concentrated α-hydroxy acid solution [3].

[0029] If the α-hydroxy acid is lactic acid, stream [3] preferably has atotal acid content of at least 80% by weight, more preferably at least90% by weight and in particular 90 to 95% by weight. The chiral purityof the solution is then at least 90%, more preferably at least 95% andin particular at least 98%.

[0030] If the α-hydroxy acid is glycolic acid, stream [3] preferably hasa total acid content of at least 70% by weight, more preferably at least80% by weight and in particular 85 to 95% by weight. As will be clear tothe expert, in the case of glycolic acid the chirality is unimportant.

[0031] Total acid content (TA) is the acid content after saponificationof intermolecular ester bonds with an excess base and is determined byback titration with acid. The total acid content thus gives the quantityof monomeric, dimeric and polymeric lactic acid and is expressed as thepercentage by weight of monomeric lactic acid. The free acid content(FA) is determined by direct titration with base, i.e. beforesaponification of the intermolecular ester groups. The content ofmonomeric lactic acid (MM) is here defined as:

MM=TA−2×(TA-FA)

[0032] provided that TA-FA<10%. This means that not very much dimeric orpolymeric lactic acid can be present. It is also asked that thenon-monomeric lactic acid is present in the form of lactoyl lactic acid(dimer).

[0033] Chiral purity (for an excess (S)-isomer) is here defined as:

Chiral purity=100% ×{((S)-isomer)/(R)isomer+(S)-isomer)}

[0034] With the method according to the invention an α-hydroxy acid canbe obtained which is both colourless and chirally pure. The degree ofcoloration is determined in accordance with ASTM D 5386-93 and is in“APHA units”. The method is suitable for determining coloration of clearliquids. A coloration of at least 10 APHA units means that the relevantliquid has a visually imperceptible coloration and is thus colourless asobserved with the naked eye. The coloration is also determined afterhearing (for approximately two hours under reflux).

[0035] Advantages of the present invention are that α-hydroxy acid canbe obtained with a high purity and with a high yield per unit of weightof the supplied feed per unit of time. In addition, with the methodaccording to the present invention, α-hydroxy acid can be obtained witha colour (after heating for two hours under reflux cooling of not morethan 50 APHA, preferably not more than 25 APHA and in particular notmore than 10 APHA (these values apply to an α-hydroxy acid solutionwhich contains 92% by weight pure α-hydroxy acid). Another advantage ofthe present invention is that the first extraction step (i) of step (a)can be performed under atmospheric pressure. A further advantage ofworking at atmospheric pressure during the extraction is a shortresponse time (the system rapidly reaches equilibrium), as a result ofwhich the method can be effectively monitored and effectively controlledand is less sensitive to interference. In addition, it is easier toscale up the method to a large-scale industrial process. Finally, theextraction is simpler than corresponding extractions which are knownfrom the prior art, because only liquid/liquid systems are involved andit has been found that relatively impure aqueous streams containingα-hydroxy acid, i.e. streams which for example contain large amounts ofresidual sugars, can be efficiently purified in this way.

[0036] FIG. 1 shows a preferred embodiment of the process according tothe invention.

[0037] According to FIG. 1, an aqueous stream containing mainlyα-hydroxy acid [1] is subjected to a first extraction, with stream [5]containing the extraction agent. The α-hydroxy acid is thus extractedfrom the aqueous phase to the organic phase (stream [6]), with theaqueous phase mainly containing contaminants and a small quantity ofα-hydroxy acid (stream [7]). Stream [6] is subjected to a secondextraction with the formation of an aqueous phase containing mainlyα-hydroxy acid (stream [2] and an organic phase containing mainlyextraction agent [9]. Finally [2] is concentrated by evaporation ofwater, forming the concentrated α-hydroxy solution in water [3].

[0038] According to FIG. 1, stream [6] is subjected to a washing stepwith water, in which any remaining contaminants soluble in water areremoved from the organic phase containing α-hydroxy acid. In thiswashing step it is unavoidable that a small quantity of α-hydroxy acidis also washed out of the organic phase (stream [6]), so that stream[10] is preferably fed back into the process, in particular before step(a) of the present method. Furthermore, the organic phase, containingmainly extraction agent, which is formed after the second extraction(stream [9] is preferably washed with an aqueous solution of aninorganic base of an alkali metal, preferably sodium hydroxide, in orderto remove any acid and other contaminants still present from stream [9].The stream so purified [9] can be used again for the first extraction,i.e. be applied as a feed for stream [5]. In the purification of stream[9] an aqueous [11] is released which is discharged as a waste stream.

[0039] The aqueous stream [7] which is formed during the firstextraction step (forward extraction) preferably contains at least 90% byweight water, calculated in terms of the complete mixture, and inparticular at least 95% by weight water. In addition, stream[7]preferably contains not more than 5% by weight α-hydroxy acid. For anefficient extraction stream [7] is the fed back into the process beforestep (a). In addition, the first aqueous phase containing mainlycontaminants [7] is concentrated by evaporation of water before thisstream is further processed, either as a waste stream or as a feedbackstream.

[0040] According to another preferred embodiment of the invention, theconcentration of stream [7] can be omitted. In this case a concentrationstep is performed before step (a), with stream [1] being concentrated insuch a way that an aqueous stream containing concentrated α-hydroxy acidis obtained which contains 40 to 50%a by weight α-hydroxy acid,calculated in terms of the whole stream. This aqueous stream containingconcentrated αhydroxy acid is then subjected to the first extractionstep, with a stream [7] being formed which contains mainly only waterand contaminants.

[0041] Step (i) of the method according to the invention is preferablycarried out at atmospheric pressure and at a temperature of 0° to 60° C.in particular at a temperature of 10° and 50° C. If the extraction agentdoes not contain any alcohol and/or ketone, however, step (i) ispreferably carried out at atmospheric pressure and at a temperature of60° to 100° C. The volumetric ratio of the aqueous stream containingmainly α-hydroxy acid [1] and the mainly water-insoluble streamcontaining the extraction agent [5] is preferably between 20:1 and 1:20,more preferably between 3:1 and 1:7 and in particular between 2:1 and1:5.

[0042] Step (ii) of the method according to the invention is preferablycarried out at a pressure of 1 to 10 bar, in particular at a pressure of2 to 9 bar, and a temperature of 100° C. to 180° C., in particular atemperate of 120° and 160° C. The volumetric ratio of the organic phasecontaining mainly α-hydroxy acid and extraction agent [6] and theaqueous stream [8]—step (ix)—is preferably between 20:1 and 1:20, morepreferably between 3:1 and 1:7 and in particular between 2:1 and 1:5,and especially between 1:2 and 1:4.

[0043] The extraction agent which is used in step (i) of 1the methodaccording to the present invention preferably comprises (1) an amine and(2) a hydrocarbon. The extraction agent preferably also comprises (3) analcohol and/or a ketone. It has furthermore been found that good resultscan also be achieved with isopropyl ether, as, is described for examplein U.S. Pat. No. 1,906,068, which is here recorded for referencepurposes. As has been noted, the conditions under which step (i) of themethod according to the invention is carried out are various. If theextraction agent does not contain any alcohol and/or ketone, step (i) ispreferably carried out at atmospheric pressure and at a temperature of60° to 100° C. Otherwise step (i) is preferably carried out atatmospheric pressure and at a temperature of 0° to 60° C., in particularat a temperature of 10° and 50° C.

[0044] The amine is preferably a tertiary amine with at least 18 carbonatoms and preferably contains 24 to 42 carbon atoms. If the extractionagent contains an alcohol, which is preferable, the alcohol is a C₈-C₁₂alcohol.

[0045] The hydrocarbon is preferably a petroleum fraction which consistsof saturated alkanes and preferably has a flash point of at least 40°C., more preferably of at least 70° C. and in particular a flash pointof at least 90° C. A higher flash point has the advantage that lessstringent safety requirements need to be set for the equipment used instep (a). The boiling range of the hydrocarbon is preferably 150° to275° C., in particular 170° to 260° C. The hydrocarbon is in particularIsopar K™ or Isopar M™.

[0046] The extraction agent preferably contains 40 to 75% by weight (1),5 to 60% by weight (2) and 0 to 25% by weight (3), and in particular 45to 55% by weight (1) 45 to 55% by weight (2) and 0 to 10% by weight (3).

[0047] Step (b) of the method according to the invention is preferablycarried out in one or more falling-film evaporators and/or thin-filmevaporators and/or smeared-film evaporators, with step (b) preferablybeing carried out at atmospheric pressure to a pressure of 0.1 bar, inparticular 0.8 to 0.2 bar and at a temperature from 25° to 140° C., morepreferably from 40° to 100° C. and in particular 60° to 85° C. Stream[2] is preferably at a pressure from 0.5 to 1 bar, in particular from0.7 to 0.9 bar, and a temperature of 50° to 100° C., in particular from70° to 90° C.

[0048] The known crystallization techniques can in principle be appliedin step (c). An example of such a technique is melting crystallization(or cooling crystallization), where the condensed, liquid concentrate ordistillate, which for example contains the (S)-α-hydroxy acid or(R)-α-hydroxy acid in a molten state, is directly cooled, so that the(S)- or (T)-α-hydroxy acid crystallizes out. It is preferable to keepthe temperature at which crystallization occurs (the crystallizationtemperature) as low as possible, so that the formation of oligomers andpolymers of the α-hydroxy acid is limited as much as possible.

[0049] Melting crystallization is a process in which a crystallinematerial is obtained from a melt of the material to be crystallized.This technique is for example described in detail in Kirk-Othmer,Encyclopedia of Chemical Technology, fourth edition, Part 7, pages723-727 (1993), in J. W. Mullin, “Crystallization”, third revisededition, Butterworth-Heinemann Ltd, pages 309-323 (1993) and in J.Ulrich and B. Kallies, Current Topics in Crystal Growth Research, 1(1994), which have been recorded here for reference. The main advantageof melting crystallization relative to distillation is that much lessenergy is needed, because the enthalpy of melting of organic compoundsis generally lower than the enthalpy of evaporation. This advantage alsooccurs with other crystallization techniques, because the enthalpy ofcrystallization is usually lower than the enthalpy of evaporation.Another advantage of melting crystallization relative to distillation isfurthermore that the process can generally be carried out at a muchlower temperature—which is advantageous when the organic compound isthermally unstable.

[0050] The melting crystallization can be carried out with the aid of asuspension crystallization or a layer crystallization, if necessary incombination with a washing column or a centrifuge, or anotherpurification technique. Examples of suitable equipment and processes aredescribed in Kirk-Othmer, Encyclopedia of Chemical Technology, fourthedition, Part 7, pages 723-727 (1993), in J. W. Mullin,“Crystallization”, third revised edition, Butterworth-Heinemann Ltd.,pages 309-323 (1993) and J. Ulrich and B. Kallies, Current Topics inCrystal Growth Research, 1 (1994), the content of which has beenrecorded here for reference.

[0051] It has also been found that crystallization of an aqueoussolution gives very good results. In this crystallization treatment theconcentrated lactic acid solution is diluted with water and this is thensubjected to one or more cooling and/or evaporative crystallizationsteps. In these techniques the concentrate or distillate is directlycooled (cooling crystallization) or concentrated by evaporation of water(evaporative crystallization). The driving force for the crystallizationin the cooling crystallization technique is the bringing about ofsupersaturation in the concentrated lactic acid solution by reducingtemperature of the concentrated lactic acid solution. As a result of thelower temperature of the solution the solubility decreases andsupersaturation occurs.

[0052] The driving force for the crystallization in the evaporativecrystallization technique is the bringing about of supersaturation inthe concentrated lactic acid solution by evaporation of water, as aresult of which the concentration of the solution increases while thetemperature remains constant. Crystallization of the lactic acid thenoccurs during the evaporation of water.

[0053] Another highly stable crystallization technique is adiabaticcrystallization, where the driving force for the crystallization is thebringing about of supersaturation in the concentrated lactic acidsolution by evaporation of water without supplying heat. The evaporationof water has two effects: (a) the temperature of the concentrated lacticacid solution becomes lower and (b) the concentration of the acidincreases. Both effects lead to a decrease in the solubility and anincrease in the supersaturation.

[0054] Crystallization step (c) is preferably carried out according tothe invention by means of adiabatic crystallization or coolingcrystallization, in particular by means of adiabatic crystallization.Seed crystals are preferably added to the concentrated lactic acidsolution in the crystallization.

[0055] The lactic acid which is crystallized out can then be separatedby the known methods for solid-liquid separation from the remaining, ormother liquor.

[0056] Examples of suitable separation techniques for separating thelactic acid crystals from the mother liquor are centrifugation,decanting, filtration, separation by means of one or more washingcolumns, or a combination of two or more of these techniques. In thecontext of the invention it has been found that centrifugation andseparation with one or more washing columns is particularly appropriate.

[0057] The mother liquor which is obtained still contains considerablequantities of lactic acid. For optimal process management it istherefore preferable to feed this mother liquor back into the process.

[0058] After isolation the lactic acid crystals which are obtained aredirectly dissolved in a suitable solvent, usually water, in order toprevent coagulation of the hygroscopic lactic acid crystals occurring.The concentration of the lactic acid solution so obtained can inprinciple have any desired concentration. In practice this will usuallyvary from 30 to 95%. Concentrations commonly occurring on the market are80-90%.

[0059] The invention also relates to an α-hydroxy acid or an α-hydroxyacid solution with a chiral purity of at least 99% and a colour of notmore than 10 APHA units, with the α-hydroxy acid or the α-hydroxy acidsolution having an acceptable odour, in particular for pharmaceuticalapplications. In the case of an α-hydroxy acid solution the solvent ispreferably water. The chiral purity, if applicable, is preferably atleast 99%, in particular at least 99.5%, which corresponds to 99%enantiomeric excess (ee) or higher. Most preferable is lactic acid, orthe solution thereof, whose chiral purity is at least 99.8% (i.e. atleast 99.6% ee).

[0060] The α-hydroxy acid or the α-hydroxy acid solution also meets thefollowing requirements:

[0061] alcohol content: not more than 250 ppm (alcohol is methanol,ethanol or other alcohol, as alcohol as such or in the form of alactate).

[0062] total nitrogen: not more than 5 ppm.

[0063] total sugar: not more than 100 ppm.

[0064] organic acids (other than lactic acid); not more than 250 ppm.

[0065] With regard to odour the α-hydroxy acid or the α-hydroxy acidsolution possesses a considerable improvement for application in foodsand a higher chemical purity than the products according to the priorart.

[0066] The α-hydroxy acid according to the invention can be both(S)α-hydroxy acid and (R)-α-hydroxy acid, depending on the microorganismwhich is used in the fermentation.

[0067] Because of their high chiral purity both the (S)-α-hydroxy acidand the (R)-α-hydroxy acid or the solutions thereof can very suitably beapplied for syntheses. The chirally pure (S)-α-hydroxy acid or solutionsthereof are also very suitable for being applied in pharmaceuticalpreparations.

[0068] The invention therefore also relates to a pharmaceuticalpreparation which contains the (S)-α- hydroxy acid described above orthe (S)-α-hydroxy acid. The invention is now illustrated by means of thefollowing example.

EXAMPLE 1

[0069] An (S)-lactic acid solution as obtained on an industrial scalewith the method which is described in Netherlands Patent Application1013265 is used as the starting material. This method comprisesfermentation to lactic acid, processing of the fermentation medium byacidification and removal of the salts so formed. This gives a lacticacid solution which is then subjected to an extraction step according tostep (a) of the method according to the present invention. After theextraction the solution is treated with activated charcoal to remove anyextraction agent present. The properties of the lactic acid solutionwere as follows: Total acid 42.1% Monomeric acid 41.2% Colour (fresh)132 APHA

[0070] The solution is then concentrated using a KDL-4 short-pathdistiller (conditions: oil bath 130° C., feed rate 10 ml/min, pressure100 mbar, rotor speed 250 r.p.m. cooling water is tap water). The lacticacid concentration of the deposit was about 91% by weight calculated interms of the deposit.

[0071] The crystallization was performed as follows. 327 g of theconcentrated lactic acid was put into a three-necked round-bottomedflask and the flask was placed in a thermostat bath. At 31° C. thesolution was inoculated with 0.12 g of a suspension of very small lacticacid crystals. The flask was cooled to 30° C. while stirring, and theseed crystals we left to grow for 20 min at this temperature. Thesuspension was further cooled as follows: from 30° to 26° C. in 2 hours,followed by cooling to 15° C. in 3 hours. After crystallization thesuspension was centrifuged (Sieva laboratory centrifuge, Hermle), giving150 g of lactic acid crystals. This means that the yield is 54%(calculated in terms of lactic acid). The crystals were dissolved in asmall quantity of water, giving a solution of 90% by weight lactic acid.The colour (fresh) was 8 APHA and 15 APHA (after heating), respectively.

1. Method for the purification of an hydroxy acid on an industrialscale, in which the method involves: (a) subjecting an aqueous streamcontaining mainly α-hydroxy acid [1] to an extraction step, with theformation of an aqueous phase containing mainly α-hydroxy acid [2]. (b)concentrating the aqueous phase containing mainly α-hydroxy acid [2] bymeans of evaporation of water under reduced pressure, with the formationof a concentrated α-hydroxy acid solution in water [3], and (c)subjecting the concentrated α-hydroxy acid solution [3] to acrystallization, with formation of pure α-hydroxy acid [4], where (i)the concentrated α-hydroxy acid solution [3] is directly cooled in amelting crystallizaion device, and/or (ii) the concentrated α-hydroxyacid solution [3] is diluted with water and crystallization is broughtabout in one or more cooling crystallization devices and/or evaporativecrystallization devices, and/or (iii) crystallization is brought aboutin one or more adiabatic crystallization devices.
 2. Method according toclaim 1, in which the α-hydroxy acid is lactic acid or glycolic acid. 3.Method according to claim 2, in which the α-hydroxy acid is lactic acid.4. Method according to one of the preceding claims, in which the aqueousphase containing mainly α-hydroxy acid [2] contains 0.1 to 25% by weightα-hydroxy acid and has a colour of not more than 100 APHA units. 5.Method according to one of the preceding claims, in which the aqueousphase containing mainly α-hydroxy acid [2] has a colour of not more than100 APHA units.
 6. Method according to one of the preceding claims, inwhich the aqueous phase containing mainly α-hydroxy acid [2] contains 30to 80% by weight α-hydroxy acid, calculated in terms of the whole streamwith this stream having a colour which is not more than 200 APHA units.7. Method according to one of the preceding claims, in which step (a)comprises the following component steps: (i) subjecting an aqueousstream containing mainly α-hydroxy acid [1] to a first extraction step,where the aqueous stream containing mainly α-hydroxy acid [1]is broughtinto contact with a stream which is mainly insoluble in water and whichcontains an extraction agent [5], with the formation of an organic phasecontaining mainly α-hydroxy acid and extraction agent [6] and a firstaqueous phase containing mainly contaminants [7], and (ii) subjectingthe organic phase containing mainly α-hydroxy acid and extraction agent[6] to a second extraction step, where the organic phase containingmainly α-hydroxy acid and extraction agent [6] is brought into contactwith an aqueous stream [8], with the foundation of an aqueous phasecontaining mainly α-hydroxy acid [2] and an organic phase containingmainly extraction agent [9], with the organic phase containing mainlyextraction agent [9] being fed back to step (i).
 8. Method according toone of the preceding claims, in which the organic phase containingmainly α-hydroxy acid and extraction agent [6] is subjected to a washingstep with water before step (ii), with formation of an aqueous phasecontaining mainly contaminants [10].
 9. Method according to claim 9, inwhich the aqueous phase containing mainly contaminants [10] is fed backinto the process before step (a).
 10. Method according to one of thepreceding claims, in which step (i) is carried out at atmosphericpressure and at a temperature of 0° to 60° C.
 11. Method according toone of the preceding claims, in which step (i) is carried out atatmospheric pressure and a temperature of 60° to 100° C.
 12. Methodaccording to one of the preceding claims, in which the volumetric ratioof the aqueous stream containing mainly α-hydroxy acid [1] and themainly water-insoluble stream containing the extraction agent [5] isbetween20:1and 1:20.
 13. Method according to one of the precedingclaims, in which step (ii) is carried out at a pressure of 1 to 10 barand a temperature of 100° C. to 180° C.
 14. Method according to one ofthe preceding claims, in which the volumetric ratio of the organic phasecontaining mainly α-hydroxy acid and extraction agent [6] and theaqueous stream [8] is between 20:1 and 1:20.
 15. Method according to oneof the preceding claims, in which the extraction agent comprises a (1)amine and (2) a hydrocarbon.
 16. Method according to claim 15, in whichthe extraction agent comprises (3) an alcohol and/or a ketone. 17.Method according to claim 16, in which the extraction agent contains 40to 75% by weight (1), 5 to 60% by weight (2) and 0 to 25% by weight (3).18. Method according to one of the preceding claims, in which theconcentrated α-hydroxy acid solution [3] has a total acid content of atleast 70% by weight and a monomeric α-hydroxy acid content of at least70% by weight, calculated in terms of the whole feed stream, and, ifapplicable, a ratio of the α-hydroxy acid enantiomers which is not equalto
 1. 19. Method according to one of the preceding claims, in which step(b) is carried out in one or more falling-film evaporators and/or thinfilm evaporators and/or smeared-film evaporators.
 20. Method accordingto one of the preceding claims, in which step (b) is carried out at apressure from atmospheric pressure to 0.1 bar and at a temperature of25° to 140° C.
 21. Method according to one of the preceding claims, inwhich the crystallization step (c) is carried out in one or more coolingcrystallization devices, evaporative crystallization devices and/oradiabatic crystallization devices.
 22. Method according to one of thepreceding claims, in which product stream from the crystallization step(c) is separated into a mother liquor and α-hydroxy acid crystals bymeans of a solid-liquid separation, preferably centrifugation orseparation with one or more washing columns.
 23. Method according to oneof the preceding claims, in which, if applicable, the chiral purity ofthe monomeric hydroxy acid present in the aqueous stream containingmainly α-hydroxy acid [1] is at least 90%, preferably at least 95%. 24.Method according to one of the preceding claims, in which the aqueousstream containing mainly α-hydroxy acid [1]is obtained fromfermentatively prepared α-hydroxy acid.